Clostridium difficile (Cd) is an emerging pathogen of opportunistic infection in hospitals worldwide. It is the major cause of antibiotic-associated pseudo-membranous colitis and diarrhea in human.
Cd asserts its effect through two large protein toxins: toxin A (tcdA) and toxin B (tcdB), which disrupt intestinal epithelial cells. tcdA and tcdB are large (250-308 kDa) protein toxins with multiple domains. The binding of the receptor binding domain (RBD) of Cd to carbohydrates on colonic epithelial cells is an initial step in pathogenesis. tcdA and/or tcdB enters the cells through receptor-mediated endocytosis and disrupts normal signaling pathways necessary for maintaining the cells' cytoskeleton, ultimately leading to inflammation and diarrhea. Various oligosaccharides, including the trisaccharide α-Gal-(1,3)-β-Gal-(1,4)-β-GlcNAc, bind specifically to tcdA, but the native human ligand has not been definitively identified.
Patients in hospitals treated with antibiotics have high risk of Cd infection, especially in children and those over 65 years old. Cd-associated diseases incur additional health care costs and extend hospital time. Morbidity and mortality of Cd-associated diseases have increased significantly, because of changes in the virulence of the causative strains.
Therefore, there is a need for prophylactic and therapeutic agents against Cd infection and Cd-associated diseases.